: Coronary blood flow is determined by coronary vascular resistance, which is dependent on regulation of tone in microvessels by both extrinsic neurohormonal and intrinsic local vasomotor control mechanisms. Local control is imparted primarily by metabolic responses, pressure-induced myogenic responses, and flow-dependent mechanisms. The applicant has already reported that coronary arterioles respond to both metabolic and hemodynamic factors. In vivo studies have shown that any event that alters oxygen availability changes local pO2 and production of metabolites, such as adenosine. All of these factors can simultaneously influence vascular tone, especially at the microvascular level. However, this issue cannot be resolved in vivo due to various confounding factors. Therefore, using isolated vessel approaches, the present proposal will test the hypothesis that metabolic factors (i.e. oxygen and adenosine) can interact with each other to regulate vascular tone. In addition, these two factors also modulate myogenic and flow-induced responses. Within this context, the cellular mechanisms of hypoxia and adenosine-induced vasodilation, and their cooperative interaction, will be elucidated. The involvement of endothelium, release of endogenous vasoactive substances, cellular calcium, and potassium channels will be considered. The proposed studies will be performed in porcine subepicardial coronary arterioles using isolated, cannulated vessel techniques to allow pressure, flow, pO2, and concentration of vasodilators to be independently controlled. The results of these studies will increase the understanding of vasoregulatory mechanisms in the coronary microcirculation and develop the concept of interaction of metabolic and hemodynamic factors in the integrative regulation of coronary microvascular tone.